Abstract
Abstract Hepatocellular carcinoma (HCC) is the fifth most fatal malignancy worldwide. In the US alone, according to American Cancer Society, about 17,550 new cases and over 15,000 deaths are reported annually. The fork-head box gene FoxM1 is highly significant in that regard, as it is over-expressed in HCC, and its over-expression coincides with highly aggressive, poorly differentiated HCC. Moreover, over-expression of FoxM1 correlates with poorer overall survival after surgery. Previous work demonstrated that FoxM1 is essential for chemical carcinogen (DEN)-induced development of HCC. Since the Ras-pathway is frequently mutated in human liver cancers, we investigated the effects of FoxM1 deletion on the progression of oncogenic Ras-induced HCC. In the mouse model we used, HRas-V12 is expressed specifically in the adult liver under control of the Alb-promoter. In this mouse model, majority (80 to 90%) of the male mice develop HCC by 8/9 months of age. We crossed that transgenic line with FoxM1 fl/fl MxCre strain. The triple transgenic strain of mice allowed us to delete FoxM1 at specific times after Ras driven tumorigenesis, by i.p. injection of double-stranded RNA (polyIpolyC). We deleted FoxM1 at 8 months of age, and observed significant decrease in the number of tumor nodules per liver. Deletion of FoxM1 inhibited proliferation of the tumor cells. Surprisingly, we did not observe increase in cell death in FoxM1 deleted tumors. Because FoxM1 is over-expressed in highly aggressive, poorly differentiated liver cancers, we investigated whether FoxM1 is needed for maintenance of hepatic cancer stem cells. Interestingly, we discovered almost complete depletion of hepatic cancers stem cells, CD90+CD45- cells, in FoxM1 deleted tumors. These studies have exciting implications in further considerations of FoxM1 as a target of Ras depended malignancies. Citation Format: Dragana Kopanja, Akshay Pandey, Megan Kiefer, Dae-Yeul Yu, Pradip Raychaudhuri. Ras-driven HCCs are addicted to FoxM1. [abstract]. In: Proceedings of the AACR Special Conference on RAS Oncogenes: From Biology to Therapy; Feb 24-27, 2014; Lake Buena Vista, FL. Philadelphia (PA): AACR; Mol Cancer Res 2014;12(12 Suppl):Abstract nr B07. doi: 10.1158/1557-3125.RASONC14-B07
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